It has recently been shown that anti-amyloid beta peptide (A?) antibodies or agents that bind to and sequester A??in the periphery produce a "sink effect" in which brain A? levels are appreciably diminished. This peripheral clearance provides the opportunity to develop new strategies for reducing brain A? as a therapeutic treatment in Alzheimer's disease (AD). We propose to develop a novel method for treating AD in which bone marrow stem cells are infected with a lentiviral vector directing expression of the peptidase neprilysin. The infected bone marrow cells are then transplanted to a recipient whereby the recipient will express neprilysin on the surface of red blood cells. Since neprilysin efficiently degrades A?, the serum A? levels will decrease, followed by a decrease in brain A? levels through the "sink effect". To test this strategy the following specific aims are proposed: (1) to express neprilysin on red blood cells and determine its effect on plasma and brain A? levels and amyloid plaque formation in young amyloid precursor protein transgenic (APP Tg) mice. A lentivirus vector will be used to introduce neprilysin into bone marrow progenitor cells from a donor mouse and transplant these infected cells into a recipient APP Tg mice. Brain and plasma A? levels, neprilysin activity in the plasma, and amyloid plaque formation in the brain will be monitored for up to 18 months. (2) To determine if expression of neprilysin on red blood cells can reverse the number of amyloid plaques in older APP Tg mice. This aim will be essentially the same as the first except that the recipient mice will be 18-20 months old, and we will determine if clearance of plasma A? can lead to dissolution of preformed amyloid deposits in the brain. [unreadable] [unreadable] Taken together these studies represent a novel use of stem cells to provide a mechanism for the clearance of peripheral A?, which should lead to clearance of brain A??through a described "sink effect". This represents a novel and potential useful therapeutic approach for preventing and treating Alzheimer's disease. [unreadable] [unreadable]